Over 1.1 billion people worldwide are reported to be overweight. Obesity is estimated to affect over 100 million people in the United States alone. Thirty-four percent of the population in the United States over the age of twenty is considered clinically obese. While being overweight or obese presents problems (for example restriction of mobility, discomfort in tight spaces such as theater or airplane seats, social difficulties, etc.), these conditions, in particular clinical obesity, affect other aspects of health, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being overweight or obese. The estimated mortality from obesity-related conditions in the United States is over 300,000 annually (O'Brien et al. Amer J Surgery (2002) 184:4S-8S; and Hill et al. (1998) Science, 280:1371).
There is no curative treatment for being overweight or obese. Traditional pharmacotherapies for treating an overweight or obese subject, such as serotonin and noradrenergic re-uptake inhibitor, noradrenergic re-uptake inhibitors, selective serotonin re-uptake inhibitors, intestinal lipase inhibitors, or surgeries such as stomach stapling or gastric banding, have been shown to provide short-term benefits with significant rates of relapse, and have further shown harmful side-effects to patients.
More recently, certain angiogenesis inhibitors, such as TNP-470, have been investigated for use to treat obesity (Rupnick et al., U.S. Pat. No. 6,306,819). These angiogenesis inhibitors are analogs or derivatives of fumagillin, which is a known fungal metabolite produced by A. fumigatus. Analogs and derivates of fumagillin have been researched and developed because of adverse side-effects associated with administration of fumagillin to subjects and because of poor bioavailability of fumagillin, i.e., fumagillin exhibits rapid metabolic degradation and erratic levels in blood.
For example, fumagillin has traditionally been administered as an antiparasitic agent. Fumagillin has been administered in a dose range of 10 mg to 20 mg, three times a day (30 mg/day to 60 mg/day) to humans to treat amebiasis (Seneca, Am. J. Digestive Dis. (1956) 1:310-322). Fumagillin has also been administered at 60 mg/day to humans to treat intestinal microsporidiosis due to Enteroctozoon bieneusi (Molina et al. Engl J Med (2002) vol. 346 25:1963-1969). Administering fumagillin at these dosages has resulted in patients developing blood disorders, e.g., thrombocytopenia, leukopenia, and neutropenia (Molina et al. Engl J Med (2002) vol. 346 25:1963-1969 and Seneca, Am. J. Digestive Dis. (1956) 1:310-322).
Further, fumagillin has been investigated as an anti-cancer agent. A resulting side-effect of administration of fumagillin to a mouse at a dose of 33 mg/kg/day is severe weight loss, i.e., wasting (Ingbar et al. (Nature (1990) 348:555-557); see also D'Amato et al. (U.S. Pat. No. 6,017,949) and BaMaung et al. (U.S. Pat. No. 6,323,228)). Wasting is characterized by degradation and loss of adipose tissue and lean body mass (muscle tissue, bones, and organs). Substantial loss of lean body mass along with loss of excess adiposity is not a desirable consequence of any therapy, let alone a therapy for an overweight or obese subject.
There is an unmet need for methods of treating overweight or obese subjects that are safe and effective.